Herpes simplex virus (HSV) is ubiquitous among HIV+ persons and is an important opportunistic infection (OI), influencing both the clinical progression of HIV as well as enhanceing its transmission and acquisition. Our initial studies defining T cell responses to HSV among HTV+ persons have indicated that HSV-specific CD8+ T cells play a prominent role in the control of HSV reactivation at mucosal sites in HIV+ persons. In particular, those with low precursor frequencies of HSV-specific CD8+ T cells have high reactivation rates of HSV. To our surprise, HAART therapy, while increasing HSV- specific CD4+ T cell responses, had little effect upon HSV reactivation rates, indicating that HSV differs from other herpesvirus infections in this regard. Our proposed studies are directed at defining the relationship between systemic and local HSV-specific CD8+ T cell responses and mucosal reactivation rates of HSV. Specific Aim #1 will utilize recently developed technologies including ELISpot, intracellular cytokine staining and HLA/peptide tetramers, to quantitate the HSV-specific CD8+ T cell response in HSV-infected persons with acute HIV infection treated early with highly active antiretroviral therapy. These persons should have relatively intact CD4+ T cell responses to HSV and we will test the hypothesis that the rate of HSV reactivation is influenced by the frequency of HSV-specific CD8+ T cells prior to HIV acquisition. We will also measure CD8+ T cell responses in HIV-negative persons with primary HSV infection to test the hypothesis that the memory CD8+ set point established during primary infection is inversely correlated with subsequent reactivation rates of HSV even in the immunocompetent person. Specific Aim #2 will quantitate the local HSV-specific CD8+ T cell response by T cell clonotype specific assays to determine if the quantitative circulating CD8+ T cell response to HSV is directly correlated with the quantitative mucosal CD8+ T cell response. Local CD8+ T cell responses will be compared among HIV+ persons with low versus high frequencies of pCTL and in persons with low versus high rates of HSV reactivation. Specific Aim #3 will determine if the effector mechanisms (killing and cytokine/chemokine release) utilized by lesion-derived HSV-specific CD8+ T cells between HTV+ and HIV-negative persons. These proposed studies will provide novel information about the role HSV- specific CD8+ T cell responses play on mucosal reactivation of an OI and offer the potential for providing novel therapeutic approaches for disease management.